WO2023277640A1 - Composition pharmaceutique pour le traitement du cancer - Google Patents

Composition pharmaceutique pour le traitement du cancer Download PDF

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WO2023277640A1
WO2023277640A1 PCT/KR2022/009486 KR2022009486W WO2023277640A1 WO 2023277640 A1 WO2023277640 A1 WO 2023277640A1 KR 2022009486 W KR2022009486 W KR 2022009486W WO 2023277640 A1 WO2023277640 A1 WO 2023277640A1
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cancer
ppib
protein
cells
pharmaceutical composition
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PCT/KR2022/009486
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Korean (ko)
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강석구
오유정
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연세대학교 산학협력단
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/52—Isomerases (5)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/53—Ligases (6)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/9015—Ligases (6)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention relates to a pharmaceutical composition for cancer treatment.
  • Cancer is one of the most common causes of death worldwide. Approximately 10 million new cases occur each year, accounting for approximately 12% of all deaths, making it the third leading cause of death. Among various cancers, brain cancer in particular occurs regardless of age, and has a higher incidence in children than other cancers. Brain cancer is divided into primary brain cancer that develops in the brain tissue and the meninges surrounding the brain and secondary brain cancer that has metastasized from cancer that has developed in the skull or other parts of the body. Glioblastoma, the most common form of brain cancer, especially glioma ( glioma) is a tumor that accounts for 60% of primary brain tumors and has a high incidence.
  • glioma a tumor that accounts for 60% of primary brain tumors and has a high incidence.
  • glioblastoma is the most malignant, highly invasive, and exhibits an aggressive variant, resulting in a very poor prognosis. If glioblastoma is not treated promptly, it can have fatal consequences within a few weeks.
  • there is no specific treatment other than radiation therapy for brain cancer due to the inherent characteristic of the brain that it is difficult for a drug for treatment to be delivered to a target brain region by the Brain Blood Barrier.
  • the present invention was conceived to solve the above problems, and relates to a novel pharmaceutical composition for cancer treatment through the regulation of PPIB expression.
  • the pharmaceutical composition according to the present invention is expected to be widely used in the medical field because it has a remarkable therapeutic effect, especially in cancer overexpressing PPIB, among cancers.
  • One object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer containing PPIB (Peptidyl-prolyl cis-trans isomerase B) protein as an active ingredient.
  • PPIB Peptidyl-prolyl cis-trans isomerase B
  • Another object of the present invention is to provide a method for preparing a pharmaceutical composition for preventing or treating cancer by mixing PPIB protein with ubiquitin protein or E3 ligase (SMAD Specific E3 Ubiquitin Protein Ligase 2) protein.
  • PPIB protein ubiquitin protein or E3 ligase (SMAD Specific E3 Ubiquitin Protein Ligase 2) protein.
  • Another object of the present invention is to provide a method for confirming PPIB overexpression in cancer cells.
  • Another object of the present invention is to provide a method for preventing or treating cancer comprising PPIB protein as an active ingredient.
  • Another object of the present invention is to provide a method for inhibiting metastasis of cancer comprising PPIB protein as an active ingredient.
  • Another object of the present invention is to provide a use of a PPIB protein for cancer treatment.
  • cancer is characterized by uncontrolled cell growth, and by such abnormal cell growth, a cell mass called a tumor is formed and penetrates into surrounding tissues and, in severe cases, into other organs of the body. It means that it can be transferred. Scientifically, it is also called neoplasia. Cancer is an intractable chronic disease that in many cases cannot be fundamentally cured even if treated with surgery, radiation, and chemotherapy, causing pain to patients and ultimately leading to death. There are many causes of cancer, but internal factors and external factors. Although it has not been precisely clarified how normal cells are transformed into cancer cells through any mechanism, it is known that a significant number of cancers are affected by external factors such as environmental factors. Internal factors include genetic factors and immunological factors, and external factors include chemicals, radiation, and viruses. Genes involved in the development of cancer include oncogenes and tumor suppressor genes, and cancer occurs when the balance between them is disrupted by the internal or external factors described above.
  • cancer stem cell means a cancer cell in a comprehensive sense that has the ability of self-renewal or differentiation, which is a unique ability of stem cells, and is, for example, in the form of a sphere. of cancer cell populations or cancer tissues with unclear morphology and poor prognosis.
  • the “normal tumor growth conditions” refer to a state in which there is no cell stress due to sufficient nutrients (glucose) necessary for cell growth and sufficient growth conditions in the tumor microenvironment). Different from cancer cells, they proliferate at a slower rate or maintain a dormant state and may have resistance to anticancer drugs.
  • expression of transcriptional regulators such as PGC-1a is regulated unlike normal tumor cells.
  • the functions of key metabolic regulators may be different compared to normal cancer cells. It refers comprehensively to cells that acquire resistance to cell death (apoptosis) in nutrient deprivation and have invasion and/or metastasis capabilities through the regulation of these different metabolic control capacities and the cell signaling pathways mechanistically linked thereto. . However, it is not limited thereto as long as it is a cell capable of differentiating into a general cancer cell.
  • cancer cells are a concept including cancer stem cells.
  • cancer stem cell treatment means death of cancer stem cells, inhibition of cancer stem cell maintenance, inhibition of cancer stem cell malignance, and inhibition of cancer stem cell invasive activity. meaning to include
  • cancer treatment is a concept including “cancer stem cell treatment”.
  • anti-cancer agent is a general term for chemotherapeutic agents used for the treatment of malignant tumors.
  • Most anticancer drugs are drugs that inhibit the synthesis of nucleic acids or exhibit anticancer activity by intervening in various metabolic pathways of cancer cells.
  • Anticancer drugs currently used for cancer treatment are classified into six categories according to their biochemical mechanism of action.
  • Alkylating agents A highly reactive substance that has the ability to introduce an alkyl group R-CH2 into a compound. When applied to cells, most of them react with N7 of guanine in DNA to modify the DNA structure and chain. It causes cutting [ ⁇ ] to show anticancer and cytotoxic effects. Drugs belonging to this category include: 1 Nitrogen mustard class: Nitrogen mustard ⁇ Chlorambucil ⁇ Melphalan ⁇ Cyclophosphamide, etc.
  • Ethyleneimine class Thiotepa 3 Alkyl sulfonate class: Busulfan 4 Tri Azine/hydrazine: DTIC (dacarbazine)/procarbazine 5 Nitro element urea: BCNU, CCNU, methyl-CCNU, etc.
  • Metabolites Drugs belonging to this group have the effect of inhibiting metabolic processes necessary for the proliferation of cancer cells.
  • Antibiotics produced by bacteria include adriamycin, daunorubicin, bleomycin, mitomycin-C, and actinomycin-D that exhibit anticancer activity.
  • Mitotic inhibitors are mitotic phase-specific drugs that stop cell division in the metaphase of the mitotic phase. vincristine, vinblastine, VP-16-213 and VM-26.
  • Hormone drugs Some types of cancer can be treated by administering hormones. Male hormones are effective for breast cancer, female hormones for prostate cancer, and progesterone for endometrial cancer. is used for the treatment of acute lymphocytic leukemia or lymphoma, and the anti-female hormone tamoxifen is used for breast cancer.
  • Cisplatin Lisplatin, L-asparaginase, o,p-DDD, etc.
  • Chemotherapy approaches are used primarily to treat metastatic or particularly aggressive cancers.
  • Cytotoxic agents work by injuring or killing rapidly growing cells.
  • An ideal cytotoxic agent should have specificity for cancer and tumor cells, while not affecting normal cells.
  • drugs targeting specifically rapidly dividing cells both tumor cells and normal cells
  • substances that are cytotoxic to cancer cells while having only mild effects on normal cells are highly desirable. Therefore, it is necessary to develop an alternative anticancer substance that can specifically inhibit the proliferation of tumor cells, and since the characteristics of the primary organs in which cancer occurs are different, organ-specific anticancer drugs that reflect the characteristics of each tissue are needed. development is required
  • cancer means that cancer cells leave the primary organ and go to other organs
  • cancer means including “cancer stem cells”.
  • the spread of cancer to other parts of the body is largely divided into cancer tissue growing from the primary cancer and directly infiltrating surrounding organs, and distant metastasis to other organs along blood vessels or lymphatic vessels.
  • Metastasis can be regulated by inhibiting the expression of genes related to cancer development or inhibiting the protein activity of these genes.
  • cancer treatment is a concept that includes suppression of metastasis of cancer.
  • PPIB Prodyl-prolyl cis-trans isomerase B
  • PPIase Propeptide-prolyl cis-trans isomerase
  • PPIase Peptidyl-prolyl cis-trans isomerase
  • E3 ligases (E3 ligases) is an important component of the intracellular protein degradation system (Ubiquitin Proteasome System, UPS), which is a regulator of cellular protein homeostasis.
  • UPS Ultraquitin Proteasome System
  • E3 ligase the final component of the enzyme cascade consisting of ubiquitin activating enzyme (E1) and ubiquitin conjugating enzyme (E2), selectively modifies proteins by covalently binding ubiquitin to lysine, serine, threonine, or cysteine residues in E3. Protein ubiquitination plays an important role in cell signaling, digestion, DNA damage repair, endocytosis, and cell cycle progression.
  • MSLC mesenchymal stem like cell
  • MSC Mesenchymal stem cells
  • MSLC mesenchymal stem-like cells
  • stromal cell it means a cell having characteristics similar to mesenchymal stem cells. Classified according to the location obtained.
  • tMSLC tumor-derived mesenchymal stem-like cells; tumor MSLC
  • tumor MSLC tumor-derived mesenchymal stem-like cells
  • the pharmaceutical composition of the present invention means a composition administered for a specific purpose.
  • the pharmaceutical composition of the present invention comprises PPIB (Peptidyl-prolyl cis-trans isomerase B) protein or a nucleic acid encoding it as an active ingredient, and a ubiquitin protein or a nucleic acid encoding it It further comprises, or E3 ligase (SMAD Specific E3 Ubiquitin Protein Ligase 2) protein, or further comprises a nucleic acid encoding, preferably by suppressing the proliferation, maintenance, malignancy and invasiveness of neurospheres to treat brain cancer, In particular, it can effectively prevent and/or treat glioblastoma, and may include a compound involved therein and a pharmaceutically acceptable carrier, excipient, or diluent.
  • PPIB Peptidyl-prolyl cis-trans isomerase B
  • a ubiquitin protein or a nucleic acid encoding it further comprises, or E3
  • the pharmaceutical composition according to the present invention may be provided by further including a biguanide-based compound in the composition, and the biguanide-based compound is preferably phenformin, and the anticancer agent is preferably temozolomide.
  • the pharmaceutical composition according to the present invention contains 0.1 to 50% by weight of the active ingredient of the present invention based on the total weight of the composition.
  • Carriers, excipients and diluents that may be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginates, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.
  • treatment refers to a series of activities performed to alleviate or/and improve a target disease.
  • treatment inhibits the proliferation of cancer cells, including cancer stem cells, in numbers or quantities, kills cancer cells, inhibits the growth of cancer tissues, reduces the size of cancer tissues, or reduces the size of cancer tissues. It contains activities that inhibit the development of new blood vessels within the body.
  • diagnosis means confirming the presence or characteristics of a pathological state, and for the purpose of the present invention, diagnosis is to determine whether cancer has developed, proliferated, or metastasized, and the above “diagnosis” “Cancer” is meant to include “cancer stem cells”.
  • Cancer can be diagnosed by macroscopic or cytological confirmation of tissue from a patient suspected of having cancer or metastasis, and samples of tissues suspected of having cancer or metastasis (clinically, cells, blood, fluid, pleural fluid, ascites, joint fluid, pus) ( ⁇ ), secretion fluid, bile, pharyngeal mucus, urine, bile, stool, etc.), a method using a cancer-fighting antibody contained in the sample, a method of directly detecting a cancer-related protein in the sample, or a method encoding a cancer-related protein Cancer can be diagnosed by directly detecting nucleic acids.
  • Diagnostic methods using antigen-antibody binding or direct detection of cancer-related proteins include Western blot, ELISA (enzyme linked immunosorbent assay), RIA (Radioimmunoassay), radioimmunodiffusion, and Ouktero.
  • Ouchterlony immunodiffusion method rocket immunoelectrophoresis, tissue immunostaining, immunoprecipitation assay, complement fixation assay, flow cytometry (Fluorescence Activated Cell Sorter, FACS), protein chip ( protein chip), but is not limited thereto.
  • Methods for directly detecting nucleic acids encoding cancer-related proteins include RT-PCR, competitive RT-PCR, and real-time Reverse transcription polymerase reaction (Real-time RT-PCR), RNase protection assay (RPA; RNase protection assay), Northern blotting, or DNA chip, but is not limited thereto.
  • administration means introducing the composition of the present invention to a patient by any suitable method, and the administration route of the composition of the present invention is through any general route as long as it can reach the target tissue. can be administered.
  • Oral administration, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, intranasal administration, intrapulmonary administration, intrarectal administration, intracavity administration, intraperitoneal administration, intrathecal administration may be performed, but are not limited thereto.
  • the effective amount is the type of disease, the severity of the disease, the type and amount of the active ingredient and other ingredients contained in the composition, the type of formulation and the patient's age, weight, general health condition, sex and diet, administration time, administration route And it can be adjusted according to various factors including the secretion rate of the composition, the treatment period, and drugs used simultaneously.
  • the therapeutic pharmaceutical composition can be administered to the body in an amount of 50 ml to 500 ml once, and in the case of a compound, 0.1 ng/kg-10 mg/kg, and in the case of a monoclonal antibody, 0.1 ng/kg-10 mg /kg may be administered.
  • the administration interval may be 1 to 12 times a day, and in the case of administration 12 times a day, it may be administered once every 2 hours.
  • the pharmaceutical composition of the present invention may be administered alone or with other therapies known in the art, such as chemotherapy, radiation and surgery, for the treatment of desired cancer stem cells.
  • the pharmaceutical composition of the present invention may be administered in combination with other therapies designed to enhance the immune response, such as adjuvants or cytokines (or nucleic acids encoding cytokines) well known in the art.
  • Other standard delivery methods may also be used, such as biolistic delivery or ex vivo treatment.
  • antigen presenting cells for example, antigen presenting cells (APCs), dendritic cells, peripheral blood mononuclear cells, or bone marrow cells may be obtained from a patient or a suitable donor, activated in vitro with the present pharmaceutical composition, and then administered to the patient. there is.
  • APCs antigen presenting cells
  • dendritic cells dendritic cells
  • peripheral blood mononuclear cells or bone marrow cells
  • a pharmaceutical composition for preventing or treating cancer comprising a PPIB (Peptidyl-prolyl cis-trans isomerase B) protein or a nucleic acid encoding the same is provided, wherein the cancer has PPIB compared to normal cells. It provides a pharmaceutical composition for preventing or treating cancer, which is an overexpressed cancer, and the pharmaceutical composition further comprises a ubiquitin protein or a nucleic acid encoding the same.
  • PPIB Peptidyl-prolyl cis-trans isomerase B
  • the pharmaceutical composition provides a pharmaceutical composition for preventing or treating cancer, further comprising SMAD Specific E3 Ubiquitin Protein Ligase 2 (SMAD Specific E3 Ubiquitin Protein Ligase 2) protein or encoding nucleic acid, wherein the cancer is brain cancer.
  • SMAD Specific E3 Ubiquitin Protein Ligase 2 SMAD Specific E3 Ubiquitin Protein Ligase 2 protein or encoding nucleic acid, wherein the cancer is brain cancer.
  • SMAD Specific E3 Ubiquitin Protein Ligase 2 SMAD Specific E3 Ubiquitin Protein Ligase 2
  • PPIB Peptidyl-prolyl cis-trans isomerase B
  • PPIB Peptidyl-prolyl cis-trans isomerase B
  • E3 ligase SAD Specific E3 Ubiquitin Protein Ligase 2
  • cancer comprising the step of administering to a subject a therapeutically effective amount of a pharmaceutical composition containing PPIB (Peptidyl-prolyl cis-trans isomerase B) protein as an active ingredient, or a nucleic acid encoding the same.
  • PPIB Peptidyl-prolyl cis-trans isomerase B
  • cancer comprising the step of administering to a subject a therapeutically effective amount of a pharmaceutical composition containing PPIB (Peptidyl-prolyl cis-trans isomerase B) protein as an active ingredient, or a nucleic acid encoding the same.
  • PPIB Peptidyl-prolyl cis-trans isomerase B
  • PPIB Peptidyl-prolyl cis-trans isomerase B
  • Brain cancer is very diverse, and it is not particularly easy to treat it because the boundary between brain cells and tumor cells is not clear. Since the pharmaceutical composition for cancer treatment containing the E3 ligase of the present invention is very effective in treating intractable brain cancer overexpressing PPIB and improving prognosis, it is expected to be widely used in the field of cancer treatment.
  • MEF mouse embryonic fibroblast
  • TMSLC tumor-derived mesenchymal stem like cell
  • TS tumorsphere
  • N nucleus
  • C cell represents the cytosol.
  • Figure 2 is a diagram showing the results of confirming PPIB expression in brain tissue of mice transplanted with TS15-88 or TS13-64 brain cancer cells according to an embodiment of the present invention.
  • FIG. 3 is a diagram showing the results of confirming the cancer treatment effect of PPIB+UB or PPIB+Smurf2 overexpression in TS15-88 or TS13-64 brain cancer cells according to an embodiment of the present invention.
  • Cont is a control (GFP)
  • PPIBwt is TS15-88 or TS13-64 cells themselves isolated from the patient in Example 1
  • PPIB + UB is PPIB and ubiquitin overexpressed
  • PPIB + Smurf2 indicates overexpression of PPIB and E3 ligase (SMAD Specific E3 Ubiquitin Protein Ligase 2).
  • PPIB and Ub were administered in combination, or PPIB and Smurf2 were administered in combination.
  • Example 1 Brain cancer tumor cell culture, and animal model production
  • Tissues from newly diagnosed brain cancer patients without prior surgical intervention, chemotherapy, or radiotherapy were used in this study.
  • Single cells were isolated from human brain cancer tissue obtained after surgical treatment and then cultured as brain cancer tumor spheres according to a conventionally known method (Arch Pharm Res. 2015 Mar;38(3):402-7.).
  • Four types of human brain cancer tumorspheres (TS15-88, TS13-64, TS14-15, and TS13-68) prepared thereby and glioblastoma cell lines U87 (ATCC No.
  • HTB14 derived from human malignant glioma, and U251 (with 10% In a CO 2 , 37°C incubator, 2% B27, EGF 50ng/ml, FGF 25ng/ml, and 1% penicillin were added to DMEM-F12 50/50 medium and cultured.
  • the cultured cells were used for in vitro or in vivo experiments.
  • male nude mice (4-8 weeks old; Central Lab. Animal Inc., Seoul, Korea) whose thymus glands were removed were used, and the cultured tumor cells were injected as 5.0x10 5 single cells per mouse. to form a tumor. Tumor formation was confirmed by H&E staining.
  • Example 1 Western blotting was performed on the entire cell or by separating the nucleus and cytosol of the cell. Separation of cell nuclei and cytoplasm was performed using the NE-PERTM Nuclear and Cytoplasmic Extraction Reagents kit (#78833, Thermofisher, USA) according to the protocol recommended by the manufacturer.
  • PPIB expression rate was significantly different depending on the cell type.
  • PPIB expression was high in TS15-88 cells, and PPIB expression was low in TS13-64 cells (Fig. 1A).
  • Fig. 1A When the nucleus and cytosol of the cell were separated and tested, PPIB expression was slightly higher in the nucleus than in the cytosol in the same pattern (FIG. 1B).
  • Example 2 brain tissue was obtained from the mouse of Example 1 prepared by transplanting TS15-88 or TS13-64 cells, fixed in 10% buffered formalin, paraffin-embedded, sectioned, and then treated with Eosin and Hematoxylin ( H & E) stained. Stained tumorigenic areas were each identified under a microscope at a magnification of 4x. Additionally, tissue sections were immunostained to confirm expression of PPIB.
  • tissue sections were deparaffinized and rehydrated, formalin-fixed, washed in distilled water containing 3% H 2 O 2 for 30 minutes, and antigen retrieval was performed in 0.01M citrate butter (pH 6.0) for 20 minutes. . Thereafter, the cells were washed three times for 5 minutes each with 1x PBS, and treated with 3% BSA for 30 minutes to block non-specific binding.
  • the primary antibody was reacted with PPIB (1:200 dilution, abcam 16045; abcam, UK), and the next day after washing three times for 5 minutes with 1x PBS, the secondary anti-rabbit IgG was reacted, and the peroxidase labeled streptavidin-biotin complex and diaminobenzidine subtrate to confirm PPIB color development. Hematoxylin was counterstained and confirmed under a microscope at 40x or 200x magnification, respectively. The results are shown in FIG. 2 .
  • TS15-88 cells high PPIB expression cells
  • TS13-64 cells cells with low PPIB expression
  • TS15-88 cells high PPIB expression cells
  • TS13-64 cells cells with low PPIB expression
  • glioblastoma Compared to other brain cancers, glioblastoma is the most malignant, highly invasive, and exhibits an aggressive variant, resulting in a very poor prognosis. If glioblastoma is not treated promptly, it can have fatal consequences within a few weeks.
  • there is no specific treatment other than radiation therapy for brain cancer due to the inherent characteristic of the brain that it is difficult for a drug for treatment to be delivered to a target brain region by the Brain Blood Barrier.
  • PPIB-overexpressing brain cancer has a particularly low therapeutic effect, and therefore, there is a need to develop a treatment for PPIB-overexpressing intractable brain cancer.
  • the present invention was conceived to solve the above problems, and relates to a novel pharmaceutical composition for cancer treatment through the regulation of PPIB expression.
  • the pharmaceutical composition according to the present invention is expected to be widely used in the medical field because it has a remarkable therapeutic effect, especially in cancer overexpressing PPIB, among cancers.

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Abstract

La présente invention se rapporte à une nouvelle composition pharmaceutique pour le traitement du cancer par régulation de l'expression de PPIB. Récemment, il a été découvert qu'un effet thérapeutique est particulièrement faible dans le cas d'un cancer du cerveau dans lequel le PPIB est surexprimé et, ainsi, il a été nécessaire de développer un agent thérapeutique pour le cancer du cerveau réfractaire qui surexprime le PPIB. La composition pharmaceutique selon la présente invention a un effet thérapeutique remarquable, notamment dans les cancers surexprimant le PPIB parmi les cancers, et l'on s'attend donc à ce qu'elle soit largement utilisée dans le domaine médical.
PCT/KR2022/009486 2021-07-02 2022-07-01 Composition pharmaceutique pour le traitement du cancer WO2023277640A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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